ArticleAntimicrobial agents and chemotherapy2010
Mutational analysis of VIM-2 reveals an essential determinant for metallo-beta-lactamase stability and folding.
Article in Antimicrobial agents and chemotherapy, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 60 citations in OpenAlex.
- Multidomain DNA-Protein Mining Reveals Polymorphic Variations in RhlB Enhancing Monorhamnolipid Biosynthesis.ACS synthetic biology · 2026Article
- Molecular basis of ampicillin resistance: combinatorial mechanisms and future strategies.World journal of microbiology & biotechnology · 2026Review
- Molecular and Kinetic Characterization of MOX-9, a Plasmid-Mediated Enzyme Representative of a Novel Sublineage of MOX-Type Class C β-Lactamases.Antimicrobial agents and chemotherapy · 2022Article
- Emergence and Evolution of Unique Plasmids HarboringMicrobiology spectrum · 2022Article
- Identification of a Stable Chromosomal Tandem Multicopy ofJournal of bacteriology · 2022Article
- Emergence of Carbapenem-resistant Clinical Isolates ofJuntendo Iji zasshi = Juntendo medical journal · 2022Review
- Detection and Characterization of VIM-52, a New Variant of VIM-1 from a Klebsiella pneumoniae Clinical Isolate.Antimicrobial agents and chemotherapy · 2021Article
- Metallo-β-lactamases in the Age of Multidrug Resistance: From Structure and Mechanism to Evolution, Dissemination, and Inhibitor Design.Chemical reviews · 2021Review
- Emergence of Carbapenem-Resistant Providencia rettgeri andAntimicrobial agents and chemotherapy · 2020Article
- Virtual screening identifies broad-spectrum β-lactamase inhibitors with activity on clinically relevant serine- and metallo-carbapenemases.Scientific reports · 2020Article
- 4-(Biomolecules · 2020Article
- Article
- Isonitrile-Based Multicomponent Synthesis of β-Amino Boronic Acids as β-Lactamase Inhibitors.Antibiotics (Basel, Switzerland) · 2020Article
- VNRX-5133 (Taniborbactam), a Broad-Spectrum Inhibitor of Serine- and Metallo-β-Lactamases, Restores Activity of Cefepime inAntimicrobial agents and chemotherapy · 2020Article
- Virtual Screening and Experimental Testing of B1 Metallo-β-lactamase Inhibitors.Journal of chemical information and modeling · 2018Article
- TEM-184, a Novel TEM-Derived Extended-Spectrum β-Lactamase with Enhanced Activity against Aztreonam.Antimicrobial agents and chemotherapy · 2018Article
- Computational and biological profile of boronic acids for the detection of bacterial serine- and metallo-β-lactamases.Scientific reports · 2017Article
- Structural Insights into TMB-1 and the Role of Residues 119 and 228 in Substrate and Inhibitor Binding.Antimicrobial agents and chemotherapy · 2017Article
- Discovery of 1-Hydroxypyridine-2(1H)-thione-6-carboxylic Acid as a First-in-Class Low-Cytotoxic Nanomolar Metallo β-Lactamase Inhibitor.ChemMedChem · 2017Article
- Crystal Structure of the Pseudomonas aeruginosa BEL-1 Extended-Spectrum β-Lactamase and Its Complexes with Moxalactam and Imipenem.Antimicrobial agents and chemotherapy · 2016Article
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Authors and funding
8 authors at 3 institutions in 3 countries.
Funding
Abstract
Metallo-beta-lactamase (MBL)-producing bacteria are emerging worldwide and represent a formidable threat to the efficacy of relevant beta-lactams, including carbapenems, expanded-spectrum cephalosporins, and beta-lactamase inactivator/beta-lactam combinations. VIM-2 is currently the most widespread MBL and represents a primary target for MBL inhibitor research, the clinical need for which is expected to further increase in the future. Using a saturation mutagenesis approach, we probed the importance of four residues (Phe-61, Ala-64, Tyr-67, and Trp-87) located close to the VIM-2 active site and putatively relevant to the enzyme activity based on structural knowledge of the enzyme and on structure-activity relationships of the subclass B1 MBLs. The ampicillin MIC values shown by the various mutants were affected very differently depending on the randomized amino acid position. Position 64 appeared to be rather tolerant to substitution, and kinetic studies showed that the A64W mutation did not significantly affect substrate hydrolysis or binding, representing an important difference from IMP-type enzymes. Phe-61 and Tyr-67 could be replaced with several amino acids without the ampicillin MIC being significantly affected, but in contrast, Trp-87 was found to be critical for ampicillin resistance. Further kinetic and biochemical analyses of W87A and W87F variants showed that this residue is apparently important for the structure and proper folding of the enzyme but, surprisingly, not for its catalytic activity. These data support the critical role of residue 87 in the stability and folding of VIM-2 and might have strong implications for MBL inhibitor design, as this residue would represent an ideal target for interaction with small molecules.
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